Rheumatoid arthritis (RA), a chronic inflammatory disease of the synovial joints, afflicts up to 1.0% of the adult population worldwide, yet our understanding of the etiology and pathogenesis of RA remains limited. In RA, synovial inflammation results in growth of the synovial lining to form pannus tissue, which contributes to cartilage and joint destruction.
Although RA involves autoimmune reactions, the precise cause is unknown; and many factors may contribute. A genetic predisposition has been identified and, in white populations, localized to a shared epitope in the HLA-DR β1 locus of class II histocompatibility antigens. Unknown environmental factors, e.g., viral infections, smoking, etc. are also thought to play a role. RA is characterized by the production of, autoantibodies, including rheumatoid factor (RF; IgM antibody against the Fc portion of IgG) and anti-citrullinated protein antibodies (ACPAs) that have binding specificity for citrulline-containing proteins such as perinuclear factor, vimentin, filaggrin and fibrinogen. Prominent immunologic abnormalities include immune complexes produced by synovial lining cells and in inflamed blood vessels. Macrophages also migrate to diseased synovium in early disease; increased macrophage-derived lining cells are prominent along with vessel inflammation.
In chronically affected joints, the normally thin synovium thickens and develops many villous folds. The synovial lining cells produce various materials, including collagenase and stromelysin, which contribute to cartilage destruction, and IL-1 and TNF-α, which stimulate cartilage destruction, osteoclast-mediated bone absorption, synovial inflammation, and prostaglandins. Fibrin deposition, fibrosis, and necrosis are also present.
Rheumatoid factors (RF), antibodies to human γ-globulin, are present in about 70% of patients with RA. However, RF, often in low titers, occurs in patients with other diseases, including other connective tissue diseases such as systemic lupus erythematosus, granulomatous diseases, chronic infections such as viral hepatitis, subacute bacterial endocarditis, and tuberculosis, and cancers. Low RF titers can also occur in a small percentage of the general population, and more commonly in the elderly.
Another disease indicator is the presence of anti-CCP (cyclic citrullinated peptide) antibodies, which have a high specificity and sensitivity for RA and, like RF, predict a worse prognosis.
Diagnostic methods for predicting the severity of rheumatoid arthritis are of great clinical interest. The present invention addresses this issue.
Publications
Autoantibody profiles and uses thereof are described in U.S. Patent application, publication US-2003-0003516-A1, herein incorporated by reference.
Epitope spreading to citrullinated antigens in mouse models of autoimmune arthritis and demyelination is described by Kidd et al. (2008) Arthritis Res Ther. 10(5):R119. Zhao et al. (2008) Arthritis Res Ther. 10(4):R94 describe immune complexes contain citrullinated fibrinogen. Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice is described by Hill et al. (2008) J Exp Med. 205(4):967-79. Proteomic analysis of secreted proteins in early rheumatoid arthritis is described by Hueber et al. (2007) Ann Rheum Dis. 66(6):712-9. Antigen microarray profiling of autoantibodies in rheumatoid arthritis is described by Hueber et al. (2005) Arthritis Rheum. 52(9):2645-55.